1197953-49-3|(2-((2,5-Dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide| Ambeed

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Quality Control of [ 1197953-49-3 ] Purity: 96% SDS Specification

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Product Details of [ 1197953-49-3 ]

CAS No. :	1197953-49-3
Formula :	C₁₂H₁₂Cl₂N₃OP
M.W :	316.12
SMILES Code :	CP(C)(C1=CC=CC=C1NC2=NC(Cl)=NC=C2Cl)=O
MDL No. :	MFCD29477700
InChI Key :	XIKUAKVCJMVXCI-UHFFFAOYSA-N
Pubchem ID :	88853985

Safety of [ 1197953-49-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1197953-49-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	19
Num. arom. heavy atoms	12
Fraction Csp3	0.17
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	80.56
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	64.69 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.75
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.23
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.78
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.09
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.91
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.95

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.1
Solubility	0.0249 mg/ml ; 0.0000787 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.26
Solubility	0.0173 mg/ml ; 0.0000548 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-6.23
Solubility	0.000187 mg/ml ; 0.000000593 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	Yes
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	Yes
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.94 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.31

Application In Synthesis of [ 1197953-49-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1197953-49-3 ]

[ 1197953-49-3 ] Synthesis Path-Downstream 1~35

1
[ 615-43-0 ]
[ 1197953-49-3 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .
[3]Patent: US2015/225436,2015,A1 .
[4]Journal of Medicinal Chemistry,2016,vol. 59,p. 4948 - 4964.
[5]Patent: WO2016/65028,2016,A1 .
[6]Patent: CN105330698,2016,A .
[7]Patent: WO2017/133663,2017,A1 .
[8]Patent: CN110305161,2019,A .

2
[ 1197953-47-1 ]
[ 5750-76-5 ]
[ 1197953-49-3 ]

Yield	Reaction Conditions	Operation in experiment
84.6%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4.0h;	25 mL of a one-necked flask was added DMF (3 mL),2,5,6-trichloropyrimidine (0.72 g, 3.9 mmol) was added successively with stirring,2- (dimethylphosphonino) aniline (0.5 g, 3 mmol)Anhydrous potassium carbonate (0.62 g, 4.5 mmol), heated to 60 ° C and stirred for 4 h.(30 mL x 2), the organic phase was combined, washed with water (60 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, and the organic layer was washed with ethyl acetate (30 mL) and water (30 mL) Filtered and concentrated, and the residue was passed through a silica gel column to give 0.8 g of a pale yellow solid in 84.6percent yield.
69%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5.0h;	(2-aminophenyl)dimethyl phosphorus oxide (8.76 g, 51.81 mmol), 2,4,5-trichloropyrimidine (14.92 g, 81.35 mmol), anhydrouspotassium carbonate (22.49 g, 162.29 mmol) and N,N-dimethylformamide (50 mL) were added in a 100 mLsingle-necked flask, and the mixture was heated to 60°C and reacted for 5 hours. After the reaction was completed, thereaction solution was cooled down to room temperature, added with water (30mL) and extracted with dichloromethane(100 mL 3 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered by suction, andevaporated under reduced pressure to remove the solvent. The resulting crude product was subjected to silica gelcolumn chromatography (mobile phase, dichloromethane : methanol = 40 : 1) to give (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide (11.3 g, 69.0percent yield).1H-NMR (300 MHz, CDCl3) : delta = 11.55 (s, 2H), 8.67 (dd, J = 4.4, 8.5 Hz, 1H), 8.22 (s, 1H), 7.59 (dd, J = 7.7, 8.1 Hz,1H), 1.86 (s, 3H), 1.82 (s, 3H). 13C-NMR (75 MHz, CDCl3) : delta = 156.85, 155.10, 133.05, 133.03, 129.77, 129.63, 123.56,123.40, 122.18, 122.09, 19.28, 18.33.HRMS (ESI, [M+H]+) m/z: 316.0175.
68.4%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 16 - 70℃; for 16.0h;	At 16 deg.C , Example 1K (2.50 g, 14.8 mmol) and 2,4,5-trichloropyrimidine (2.85 g, 15.5 mmol) in DMF (20mL) mixture was added DIPEA (3.82 g, 29.6 mmol). The reaction mixture was heated to 70 deg. C and stirred for 16 hours. TLC showed the reaction was complete. The reaction mixture was washed with water (50 mL) diluted (40mL × 3) and extracted with EtOAc. The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was recrystallized from ethanol to give the title compound (3.20 g, 10.1 mmol, 68.4percent yield) as a white solid.

61%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5.0h;	Step 2: Synthesis of 2:2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and potassium carbonate (3.14 eq) in DMF were stirred at 60 °C for 5 hours and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (ISCO machine) (DCM/MeOH 20: 1 ) to give 2 as a yellow solid (61 percent yield).
61%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5.0h;	2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and potassium carbonate (3.14 eq) in DMF were stirred at 60 °C for 5 hours and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (ISCO machine) (DCM/MeOH 20:1) to give 2 as a yellow solid (61 percent yield).
50%	With N-ethyl-N,N-diisopropylamine; for 12.0h;Reflux;	A solution of 2,4,5-trichloropyrimidine(1.82 g, 10 mmol), (2-aminophenyl)dimethylphosphine oxide(1.69 g, 10 mmol) and N,N-diisopropylethylamine (1.94 g, 15 mmol)in propan-2-ol (25 mL) was heated under reflux for 12 h. The solvent was removed by evaporation and the residue was dissolvedin CH2Cl2 (100 mL). The solution was washed with water andsaturated sodium chloride solution and dried, filtered andconcentrated. The residuewas purified by flash chromatography onsilica gel (0e2percent MeOH in DCM) to afford compound 51l (1.60 g,50percent). 1H NMR (400 MHz, DMSO-d6) delta 11.84 (s, 1H), 8.43 (s, 2H), 7.62(s, 2H), 7.25 (s, 1H), 1.83 (s, 3H), 1.80 (s, 3H); 13C NMR (100 MHz,DMSO-d6) d 157.01, 155.99, 142.48, 132.73, 131.47 (d, J 10 Hz),124.17 (d, J 6.0 Hz), 122.64, 122.06 (d, J 3.0 Hz), 121.73, 115.30,18.98, 18.28. HRMS (ESI, m/z) [M+H]+ calcd for C12H13Cl2N3OP:316.0173, found: 316.0175.
	With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate; In N,N-dimethyl-formamide; at 65℃;	[00369] 245-trichloropyrimidine (54.2 g, 0296 mol, 1.0 eq.), (2arninophenyl)dimethyl..phosphine oxide (50.Og, 0.296 mole, 1.0 eq.), potassium carbonate (49.lg, 0355 mol, 1.2 eq.) and tetrabutylammonium bisuifate (10.2 g. 0.03 mole, 0.1 eq.) were combined in DMF (1050 mL), and heated at 65° C for -8.0-8.5 h. During the course of heating, an offwhite suspension formed. Upon coong, the mixture was cooled to rt and filtered. The coHected solids were rinsed with DMF (2 x 50 mL), and the combined filtrates were concentrated in vacuo. The resulting residue was dissolved in EtOAc (1 .3 L) and water (350 mL). The aqueous layer was isolated and extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (20percent w/w, 500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford (2..((25dichloropyriniidin4 yl)amino)phenyl)dimethylphosphine oxide as an offwhite solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;	General procedure: To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 2.99 mmol) and (2-aminophenyl)dimethylphosphineoxide (0.323 g, 1.907 mmol) in DMF (6.36 mL) wasadded potassium carbonate (0.828 g, 5.99 mmol). The reactionmixture was stirred at 70 °C for overnight. After completion of thereaction, the resulting mixture was cooled to room temperature,quenched with water, extracted with DCM and washed with brine.The combined organic layer was dried over Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (0-20percent MeOH in DCM)to give 3f as a yellowish solid (0.178 g, 31percent).
17 g	at 75℃; for 6.0h;	2-iodoaniline (17.5 g, 79.9 mmol) and dimethyl phosphine oxide (6.9 g, 88.5 mmol) were added,Palladium acetate (0.3 g, 1.3 mmol), Xantphos (0.77 g, 1.3 mmol),N,N-diisopropylethylamine (22.7 g, 175.8 mmol), DMF (50 mL),Magnetic stirring. Under nitrogen protection, heat to 100°C for 6 hours,The 2-iodoaniline consumption was monitored by thin layer chromatography. Cool to room temperature2,4,5-trichloropyrimidine (17.5 g, 95.9 mmol) was added and the reaction was heated to 75°C for 6 hours.The reaction was complete by thin layer chromatography. Cool to room temperature, add water 300mL,Adjust pH to 5 with 5percent hydrochloric acid and extract with ethyl acetate (100 mL x 3).Wash with sodium bicarbonate solution (100 mL), wash with saturated sodium chloride solution (100 mL × 2),Dry over anhydrous sodium sulfate. It is filtered with suction and concentrated to give a crude brown solid.Recrystallization with ethyl acetate/petroleum ether (volume ratio 1:2) gave an almost white solid 17g.Yield 67.3percent.
0.7 g	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;	Compound b1-1 (0.5 g, 3 mmol) was placed in a 100 mL three-necked flask, and DMF (30 mL) was added.Then, compound b2 (0.86 g, 4.7 mmol), anhydrous potassium carbonate (1.23 g, 9.5 mmol) was added, and stirred at 60 ° C overnight.TLC showed the reaction was almost complete, cooled to room temperature, and then water (100 mL)The organic phase was washed with brine and dried over anhydrous magnesium sulfate.Concentrated through the column to give 0.7 g of a yellow solid.

References: [1]Patent: CN106188138,2016,A .Location in patent: Paragraph 0094-0096; 0106; 0107.
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 4948 - 4964.
[3]Patent: EP3381925,2018,A1 .Location in patent: Paragraph 0158.
[4]Patent: CN105330698,2016,A .Location in patent: Paragraph 0196; 0197; 0198; 0199.
[5]Patent: WO2012/151561,2012,A1 .Location in patent: Page/Page column 37-38.
[6]Patent: WO2013/169401,2013,A1 .Location in patent: Page/Page column 43-44.
[7]Patent: US2015/225436,2015,A1 .Location in patent: Paragraph 0793-0794.
[8]European Journal of Medicinal Chemistry,2017,vol. 139,p. 674 - 697.
[9]Patent: WO2016/65028,2016,A1 .Location in patent: Paragraph 00369.
[10]European Journal of Medicinal Chemistry,2017,vol. 136,p. 497 - 510.
[11]Patent: CN107522742,2017,A .Location in patent: Paragraph 0022; 0023; 0025; 0027; 0029; 0031; 0033.
[12]Patent: CN108689994,2018,A .Location in patent: Paragraph 0108; 0110; 0111.

3
[ 3385-21-5 ]
[ 1197953-49-3 ]
[ 1407520-08-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	With hydrogenchloride; In ethanol; 2-methoxy-ethanol; at 110℃;Sealed tube;	Step 1 : Synthesis of 17Compound 2 (158mg, 0.50 mmol), 1 ,3-diaminocyclohexane (57.1 mg, 0.5mmol) was dissolved in methoxyethanol (1 .6 mL) in a sealed tube and HCl/EtOH (200 mu) was added. The content was heated at 1 10 C overnight. Solvent was removed in vacuo and the residue was purified by 2 prep-TLC plate (360 mL DCM/24 mL MeOH/12 mL 7N NH3.MeOH) to give final product as a light colored solid (134 mg, yield 68 %).
68%	In 2-methoxy-ethanol;Sealed tube;	Compound 2 (158mg, 0.50 mmol), 1 ,3-diaminocyclohexane (57.1 mg, 0.5mmol) was dissolved in methoxyethanol (1.6 mL) in a sealed tube and HCI/EtOH (200 muIota) was added. The content was heated at 110 C overnight. Solvent was removed in vacuo and the residue was purified by 2 prep-TLC plate (360 mL DCM/24 mL MeOH/12 mL 7N NH3.MeOH) to give final product as a light colored solid (134 mg, yield 68 %).

References: [1]Patent: WO2012/151561,2012,A1 .Location in patent: Page/Page column 45.
[2]Patent: WO2013/169401,2013,A1 .Location in patent: Page/Page column 47-48.

4
[ 1075705-01-9 ]
[ 1197953-49-3 ]
[ 1407520-42-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With toluene-4-sulfonic acid; In pentan-1-ol; at 115℃; for 5h;	General procedure: 4-Methylbenzenesulfonic acid hydrate (77.4 mg, 0.45 mmol) was added to compound 51a (103.5 mg, 0.3 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (67.0 mg, 0.36 mmol) in 2-pentanol(3 mL). The resulting mixture was stirred at 115 C for 5 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic extracts wer ewashedwith brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography(0-5% MeOH in DCM) to afford compound 52a (74 mg, 50%) as a yellow solid.
	With trifluoroacetic acid; In iso-butanol; at 100℃;Sealed tube;	Step 3 : The above compound B (O. l g, 0.53mmol) and 4-(ortho dimethyl phosphinyl anilino) - 5- chloro - 2-chloro pyrimidine (0.17g, 0.53mmol) were dissolved in a mixture of 2-butanol (1.2mL) & trifluoroacetic acid (0.25 mL) and were heated to 100 C in a seal tube for overnight. The reaction mixture was then cooled to rt and poured into a saturated NaHC03 solution while stirring to afford an orange solid which was filtered, washed with Et20 to remove final traces of water. The product was dried to afford C (0.19g) which was directly used in the next step.
0.19 g	With trifluoroacetic acid; In iso-butanol; at 100℃;Sealed tube;	The above compound B (0.1g, 0.53mmol) and 4-(ortho dimethyl phosphinyl anilino)- 5- chloro - 2-chloro pyrimidine (0.17g, 0.53mmol) were dissolved in a mixture of 2-butanol (1.2mL) & trifluoroacetic acid (0.25 mL) and were heated to 100 C in a seal tube for overnight. The reaction mixture was then cooled to rt and poured into a saturated NaHCC solution while stirring to afford an orange solid which was filtered, washed with Et.20 to remove final traces of water. The product was dried to afford C (0.19g) which was directly used in the next step.

General procedure: To asolution of (2-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (3f) (0.1 g, 0.334 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (0.124 g, 0.667 mmol) in sec-butanol(2 mL) was added potassium carbonate (0.231 g, 1.669 mmol). Thereaction mixturewas stirred at 80 C for 10 min and then Pd2 (dba)3(0.031 g, 0.033 mmol) and Xphos (0.016 g, 0.033 mmol) were addedrapidly. The reaction mixture was stirred at 100 C for 2 h. Aftercompletion of the reaction, the resulting mixture was hot-filteredthrough Celite and washed with DCM. The filtrate was concentratedunder reduced pressure and then purified by flash columnchromatography on silica gel (0-20% MeOH in DCM) to afford 4f asa yellowish solid (0.128 g, 85%).

References: [1]European Journal of Medicinal Chemistry,2017,vol. 139,p. 674 - 697.
[2]Patent: WO2012/151561,2012,A1 .Location in patent: Page/Page column 60.
[3]Patent: WO2013/169401,2013,A1 .Location in patent: Page/Page column 61-62.
[4]European Journal of Medicinal Chemistry,2017,vol. 136,p. 497 - 510.

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[ 1407520-51-7 ]
[ 1197953-49-3 ]
[ 1407520-52-8 ]